FIELD OF INVENTION

The present invention relates to herbal, non-hormonal based intravaginal contraceptive formulations with a spermicidal component having an antimicrobial activity and the method of preparation of the same. More specifically, the present invention relates to novel pharmaceutical formulations with Sapindoside B as the active ingredient, intended for the vaginal delivery.

BACKGROUND OF THE INVENTION
Contraception is the intentional prevention of conception or impregnation through the use of various devices, agents, drugs, sexual practices, or surgical procedures. Contraception prevents from causing pregnancy and also from protecting your body from sexually transmitted diseases and infections.

Contraceptives were first used by Egyptians. The earliest record of birth control use is an ancient Egyptian set of instructions on creating a contraceptive pessary. The history of birth control began with the discovery of the connection between coitus and pregnancy. The oldest forms of birth control included coitus interruptus, pessaries and the ingestion of herbs that were believed to be contraceptive or abortifacient. The words "birth control" entered the English language in 1914 with the American reformer Margaret Sanger. In 1914, she launched The Woman Rebel, an eight page monthly newsletter promoting contraception, with the slogan "No Gods and No Masters", coining the term birth control (Galvin et al, 1998).

The most common method of contraception is sterilization. The most effective temporary methods are nearly 99% effective if used consistently and correctly. Many methods carry health risks where as the barrier devices and avoidance of intercourse during the most fertile period is found to be the safest. Hormonal contraceptives use estrogen and/or progesterone to inhibit ovulation. The "morning-after pill" (high-dose hormones) is effective even after intercourse. But the most serious side effect of oral contraceptives is the risk of blood-clotting disorders. Intrauterine devices (IUDs) are placed inside the uterus and appear to cause a mild endometrial inflammation that either inhibits fertilization or prevents a fertilized egg from implanting. Certain types of IUDs were taken off the market due to its side effects with high incidence of pelvic inflammatory disease, ectopic pregnancy, and spontaneous septic abortion. Barrier devices, such as condoms, diaphragms, cervical caps, female condoms (vaginal pouches), and vaginal sponges, prevent sperm from entering the uterus.

Condoms are by far the best available methods for contraception. A condom can be described as a protective sheath used as a contraceptive or to protect against sexually transmitted diseases. It is a nonsurgical method of male contraception marketed worldwide. The barrier methods of contraception (BMC) reduce the risk of gonorrhoea and HIV transmission. Used with spermicides, condoms are nearly 100% effective. A study was conducted to determine whether spermicide-coated condoms are associated with an increased risk of Urinary tract infection (UTI) (Fihn et al, 1996). Condoms coated with spermicide such as nonoxynol-9 were responsible for 42% of the UTIs among women who were exposed to these products. The association confirmed in this study supported by research indicating that nonoxynol-9 induces changes in the normal vaginal flora that facilitate colonization with coliform bacteria. Roddy et al. tested the effect of nonoxynol-9 (N-9) in condom lubrication on the risk of acquiring STD and genital discomfort. They concluded that plain silicone lubricated condoms are as effective as N-9 lubricated condoms. Currently, nonoxynol-9 (N-9) is the most widely used chemical spermicidal with condoms that claims protection from transmission of STDs. While the effectiveness of nonoxynol-9 as a spermicide is well known, it has only little effect as a microbicide and in fact recent data indicate that nonoxynol-9 may actually increase the risk of HIV transmission. The frequent use of nonoxynol-9 can induce lesions and ulcerations to genital mucosa, thereby increasing the probability of transmitting infectious agents. Studies have also indicated that these adverse effects of N-9 are dose related, supporting the notion that a potentially narrow margin of safety may exist for N-9. A recent report from WHO concluded that spermicides containing nonoxynol-9 do not protect against Gonorrhoea and Chlamydia. Clinical surveys have suggested that use of spermicides with antiviral activity, e.g. nonoxynol-9, will not satisfactorily restrict the spread of HIV (Cates et al, 1992), as the frequent use of nonoxynol-9 leads to the creation of vaginal lesions (genital ulcers and vulvitis), which provide entry ports for HIV particles to pass through the protective barrier of the skin and reach the bloodstream (Kreiss et al, 1992). Also the use of chemical compound as a spermicide increases the risk of Urinary tract infection (UTI).

Fertility awareness techniques have evolved from keeping track of the menstrual cycle to avoid intercourse around the time of ovulation; tracking body temperature and cervical mucus consistency can raise effectiveness to more than 80%.

There are various forms of contraception, ranging from natural family planning methods which are least invasive, to intrauterine devices which require a doctor's intervention. Creams, foams, jelly, films and pessaries with special spermicidal chemicals can be used as contraceptives. These substances are inserted into the vagina before intercourse, and essentially immobilize the sperms and make them ineffective. Another concept in the contraceptive methods in developing countries is the vaginal film formulation. This formulation is not messy in nature, can be inserted into the vagina before hand and hence does not interrupt coitus.

The optimum pH value for sperm migration and sperm survival in the cervical mucus is between 7.5 and 8.5. The formulation in the present invention changes the pH of the vaginal mucus into acidic nature and this acid mucus immobilizes sperm in the vagina and facilitates contraception (WHO Laboratory Manual for the Examination of Human Semen and Sperm-cervical Mucus Interaction, Ch. 5:51-59 (1999), which is hereby incorporated by reference in its entirety) The immobilization of sperm occurs in the vagina at a pH of 5.0 and cause the death of the sperm by creating an environment where in the sperm are irreversibly immobilized (Olmsted et al, 2000), which is hereby incorporated by reference in its entirety.

U.S. Pat. No. 5,595,980 to Brode et al. describes an improved contraceptive composition which comprises a spermicide or virucide, a polymeric delivery component and optionally a cosmetic ingredient. The improvement is directed to the use of certain hydrophobically modified polysaccharides as the polymeric delivery component. It contains a spermicide molecule called Nonoxynol-9. But it has several disadvantages as it causes vaginal or penile irritation. Other observable side effects include itching, burning or urination, slight inflammation of the vagina, pain and increased white discharge.

PCT Publication No. WO/2006/007741 to THONY describes a liquid detergent based on aqueous extracts containing saponin. This saponin extract of the novel detergent and care product is preferably obtained from the pericarp of Sapindus mukorossi or Sapindus trifoliatus.

PCT Publication No. WO/2004/019960 to ARORA et al. describes an herbal extract comprising a mixture of saponins obtained from sapindus trifoliatus for anticonvulsant activity.

U.S. Pat. No. 6,333,058 to Ilavazhagan et al. describes a process for preparing a spermicidal agent from neem oil.

EP472791 to Talwar et al. describes the use of neem oil or its components in the manufacture of a medicament for the reversible blocking of fertility in a female.

U. S. Pat. No. 5,196,197 to Talwar et al. describes an anti-fertility agent comprising neem oil and a reetha extract wherein the neem oil is present in a concentration of about 10%-25% w/w and the concentration of the reetha extract is about 0.5-1% w/w. But none of the above discloses a device along with plant derived substance for use as spermicidal and anti-infective.

244/DEL/2003 discloses a cream based herbal formulation comprising sapindus saponin ranging between 1 to 5% for local contraception.

U.S. Patent Application No. 20090041743 describes a sperm-blocking agent composition with contraceptive effect comprising an aqueous solvent gum which is a polysaccharide having about 0.3 to 10 wt % of the composition and a lubricant which contain alcohols having about 0.5 to wt % of the composition. The alcohol is at least one selected from polyethene glycol having a molecular weight of over 200, polypropylene glycol having a molecular weight poly (ethylene oxide) polymers and glycerin; wherein the viscosity of the composition is above 9000 est. But this composition blocks the sperm from moving and does not act as spermicidal. Also this sperm blocking composition is not having any activity against Trichomonas vaginalis.

Riar et al. investigated the volatile, odorous fraction of neem oil coded as NIM-76 obtained by steam distillation for in-vitro spermicidal activity and was found to inhibit spermatozoal motility at minimum concentrations of 0.25 mg/ml for rat and 25 mg/ml for human spermatozoa.

Sairam et al. showed that NIM-76 has a potent broad-spectrum anti-microbial activity. The NIM-76 preparation inhibited growth of various pathogens including Escherichia coli and Klebsiella pneumoniae, which were not affected by the whole neem oil. NIM-76 also exhibited antifungal activity against Candida albicans and antiviral activity against Poliovirus replication in vero cell lines. It also protected mice from systemic candidiasis as revealed by enhanced % survival and reduced colony forming units of C. albicans in various tissues. But this formulation is not effective against one of the sexually transmitted disease Trichomoniasis caused by Trichomonas vaginalis.

Dwivedi et al. developed HPTLC method as well as HPLC method combined with ES-MS and validated the same. They also developed a method for the quantitative determination for Sapindoside B.

B.S.Setty et al. has proved the potent spermicidal activity of saponin isolated from Sapindus mukorossi. They studied the morphological changes of human spermatozoa under Scanning Electron Microscopy after in vitro exposure to saponins isolated from Sapindus mukorossi.

Nivsarkar et al. observed the biochemical and biophysical changes in the sperm membrane during sperm maturation in male rats treated with the water extract of the fruit pericarp of Sapindus mukorossi.

Gupta et al. tested saponin extract from Sapindus mukorossi for bacteriostatic or bactericidal property against Lactobacillus acidophilus. The studies indicate that Sapindus saponin as compared to Nonoxynol-9 is far less toxic to lactobacillus species. They also stated that saponin containing spermicidal preparations are more vaginal friendly than Nonoxynol-9 preparations.

Manmohan Singh et al. studied and evaluated the anti Trichomonas activity of Sapindus saponins. Their findings demonstrate the potential of Sapindus saponins for development as a microbicidal contraceptive for human use.

Radhika et al. studied the in vitro antimicrobial activity of Sapindus mukorossi and Emblica officinalis against the Dental caries pathogens like Streptococcus mutans, Staphylococcus aureus, Lactobacillus acidophilus, Candida albicans and Saccharomyces cerevisiae.

Hence, there is a need for a novel herbal pharmaceutical contraceptive composition contains Sapindoside B as the spermicidal agent to reduce the risk of vaginal lesions and also to give protection against Trichomoniasis a Sexually transmitted disease.

OBJECTIVES OF THE INVENTION

An objective of the present invention is to formulate a novel pharmaceutical formulation containing herbal contraceptive agent with antimicrobial property in different vaginal dosage form, which eradicates the
disadvantages of the known contraceptives.

Another objective of the present invention is to formulate a novel herbal contraceptive in different vaginal dosage forms containing Sapindoside B as the active component having Spermicidal and Anti Trichomonas activity.

Another objective of the present invention is to formulate a novel non hormonal herbal contraceptive in different vaginal dosage forms containing Sapindoside B as the active component which avoids the hormonal side effects.

Yet, another objective of the present invention is to formulate a novel herbal contraceptive formulation with antimicrobial property containing Sapindoside B as the active ingredient in the form of muco-adhesive film, cream, gel, foaming pessary, a soft gelatine capsule pessary and compressed pessary.
Still another objective of the present invention is to formulate a novel herbal contraceptive formulation with antimicrobial property containing Sapindoside B as the active ingredient incorporated in the lubricant of condoms.

SUMMARY OF THE INVENTION
The present invention relates to a novel herbal contraceptive formulation for the delivery of spermicidal and anti-trichomonas agent, sapindoside B to the vaginal cavity.

The invention enables the incorporation of a non hormonal herbal contraceptive agent in various pharmaceutical formulations namely muco-adhesive film, foaming pessary, soft gelatine capsule pessary, compressed pessary, gel, cream and saponin incorporated condom lubricant which enables dose precision. The muco-adhesive film, pessary and gel dissolve in the vaginal fluid within 2-6 minutes and releases sapindoside B into the vaginal environment. Sapindoside B then elicits the spermicidal activity locally and facilitates contraception.

The present invention also relates to the non hormonal composition as it does not contain estrogen, progesterone, other steroids, or its derivatives. The novel pharmaceutical formulations act locally at the site of insertion.

The advantages of the present invention over the known contraceptives are: (a) herbal contraceptive component is non-hormonal, non-systemic and biodegradable in nature (b) greater efficacy (c) easy administration (d) easy of portability and (e) the formulation causes immobilization and death of sperm in relatively low concentrations of spermicidal agents

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the novel pharmaceutical formulations with Sapindoside B as the active ingredient. The novel pharmaceutical formulation is intended for the vaginal delivery of Sapindoside B. Sapindoside B acts as a spermicide (sperm killing agent) and is also effective against Trichomonas vaginalis which causes Trichomoniasis, a sexually transmitted disease. The novel pharmaceutical formulations act locally at the site of insertion. The present invention also relates to the non hormonal composition as it does not contain estrogen, progesterone, other steroids, or its derivatives.

In one embodiment of the present invention, the incorporation of a non hormonal herbal contraceptive agent in various pharmaceutical formulations namely muco-adhesive film, foaming pessary, soft gelatine capsule pessary, compressed pessary gel, cream and saponin incorporated condom lubricant enables dose precision. These formulations can be easily inserted into the vaginal cavity before coitus with or without an applicator according to the convenience of the user. The muco-adhesive film, pessary and gel dissolve in the vaginal fluid within 2 to 6 minutes and releases sapindoside B into the vaginal environment. Sapindoside B then elicits the spermicidal activity locally and facilitates contraception.
The advantage of the present invention is to provide a novel herbal contraceptive formulation such that, the herbal contraceptive component is non-hormonal, non-systemic and biodegradable nature which provides a method of contraception that can be used according to the need of the user. Other advantages of this invention are that the novel herbal contraceptive composition provides greater efficacy, easy administration, easy of portability than other contraceptive measures. Another advantage of the invention is that, this novel contraceptive formulation causes immobilization and death of sperm in relatively low concentrations of spermicidal agents

The examples given below serve to illustrate embodiments of the present invention. However, they do not intend to limit the scope of the present invention.

FORMULATION OF VAGINAL FILM

Vaginal film is novel type of vaginal drug delivery systems. Contraceptive vaginal film is a very thin translucent film of polymer that contains spermicide as the active component. When the film is placed in the vagina on or near cervix, it dissolves quickly delivering the spermicidal agent that kills sperms on contact.

Vaginal films were cast by solvent evaporation method on glass substrate. Aqueous solutions of biodegradable polymers were prepared under constant stirring and different concentration of plasticizers was added to the polymer solution. After the addition of plasticizer, the extract of the saponin was incorporated into the polymeric solution by stirring mechanically at room temperature for 10-12 hrs followed by centrifugation to remove the entrapped air. This solution was poured into the Petri plates followed by drying in hot air oven at 40° C. The vaginal film after drying was removed from the Petri
plates, cut in to circular films of 5cm diameter using a sharp scalpel.

The films were packed carefully by wrapping it in polyethylene laminated aluminum foil and stored at room temperature in heat sealed air tight plastic pouches. Prepared films were then optimized for getting a standard formula by evaluating its properties mainly dissolution time.

Different water soluble film forming polymers like PVA, HPMC and HPC were used to prepare film of required properties. Several plasticizers like sorbitol, glycerol and propylene glycol were tried as plasticizer to get the required consistency for the film. Placebo films were prepared by using different ratios of these polymers and the plasticizer and the best combination were selected for the formulation of film based on the dissolution time.

FORMULATION OF PESSARY

Pessaries were prepared by pour moulding. Polymer solution was prepared by melting combination of different grades of PEG in different concentrations and 0.1ml Hexane-1- ol on a water bath. The saponin extract in ethanol was incorporated into the polymer solution by stirring mechanically. The mixture was then heated at 60° C to evaporate ethanol. This mass was then poured into cooled metal moulds and allowed to set.

The pessaries were packed in a polyethylene lined blister tape packaging and store in refrigerator. Prepared pessaries are then optimized for getting a standard formula by evaluating its properties mainly disintegration time.

EXAMPLES
Example 1
5 g poly vinyl alcohol was stirred with 100 ml water to form a homogeneous polymer solution. Sapindoside B was added to the above polymer solution and stir continuously to get a uniform viscous solution. Then 13 ml of propylene glycol was added to the above solution and mixed well. The solution was poured to the cast surface and kept for drying at 40° C for 12 hours. The film was peeled from the cast surface.

Example 2
7.5 g poly vinyl alcohol was stirred with 100 ml water to form a homogeneous polymer solution. Sapindoside B was added to the above polymer solution and stirred continuously to get a uniform viscous solution. Then 16 ml of propylene glycol was added to the above solution and mixed well. The solution was poured to the cast surface and kept for drying at 40° C for 12 hours. The film was peeled from the cast surface.

Example 3
g poly vinyl alcohol was stirred with 100 ml water to form a homogeneous polymer solution. 7 ml of propylene glycol was added to this solution and mixed well. Sapindoside B was added to the above polymer solution and stir continuously to get a uniform viscous solution. 13 ml of this solution was poured to the cast surface and kept for drying at 40° C for 12 hours. The film was peeled from the cast surface.

Example 4
6 g polyethylene glycol 4000 and 4 g polyethylene glycol 400 were melted together. This mixture was cooled and Sapindoside B was added into this. Then the mixture was poured into pessary mould. The mould was cooled at 25° C. The mould was opened to collect the pessaries.

Example 5
6 g polyethylene glycol 4000 and 4 g polyethylene glycol 400 were melted together. To this mixture weighed quantities of citric acid, sodium bicarbonate and sodium lauryl sulphate was added. This mixture was cooled and Sapindoside B was added into this. Then the mixture was poured into pessary mould. The mould was cooled at 25° C. The mould was opened to collect foaming pessaries.

Example 6
6g polyethylene glycol 1500 and 4 g polyethylene glycol 400 were melted together. To this mixture weighed quantities of citric acid, sodium bicarbonate and sodium lauryl sulphate was added. This mixture was cooled and Sapindoside B was added into this. Then the mixture was poured into pessary mould. The mould was cooled at 25° C. The mould was opened to collect foaming pessaries.

Example 7
7 g polyethylene glycol 4000 and 3 g polyethylene glycol 400 were melted together. To this mixture weighed quantities of citric acid, sodium bicarbonate and sodium lauryl sulphate was added. This mixture was cooled and Sapindoside B was added into this. Then the mixture was poured into pessary mould. The mould was cooled at 25° C. The mould was opened to collect foaming pessaries.

Example 8
7 g polyethylene glycol 1500 and 3 g polyethylene glycol 400 were melted together. To this mixture weighed quantities of citric acid, sodium bicarbonate and sodium lauryl sulphate was added. This mixture was cooled and Sapindoside B was added into this. Then the mixture was poured into pessary mould.

The mould was cooled at 25° C. The mould was opened to collect foaming pessaries.

Example 9
700 mg of Polyethylene glycol 1500 and 300 mg of Polyethylene 4000 was melted at 50 °C. The drug will be added into this mixture and mixed. 0.1 ml of hexane-1-ol will be added to this. This mixture will be then poured into pessary mould and is allowed to cool to room temperature. The mould was opened to collect the pessaries.

While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed.

WE CLAIM:

1. A novel pharmaceutical formulation containing herbal contraceptive Sapindoside B with antimicrobial property in different vaginal dosage forms for reducing the risk of vaginal lesions and protection against sexually transmitted disease.

2. The formulation according to claim 1, wherein the said herbal contraceptive Sapindoside B acts as a spermicidal agent and anti-trichomonas agent.

3. The formulation according to claim 1, wherein the said sexually transmitted disease is Trichomoniasis.

4. The formulation according to claim 1, wherein the said different vaginal dosage forms are muco-adhesive film, gel, cream, foaming pessary, soft gelatine capsule pessary, compressed pessary and saponin incorporated condom lubricant.

5. The formulation according to claim 1, wherein the said formulation causes immobilization and death of sperm even in relatively low concentrations of spermicidal agents.

6. The formulation according to claim 1, is non-hormonal, non-systemic and biodegradable in nature.

7. A novel pharmaceutical composition comprising non-hormonal herbal contraceptive Sapindoside B with antimicrobial property to reduce the risk of vaginal lesions and give protection against sexually transmitted disease.

8. The composition according to claim 7, wherein the said non-hormonal herbal contraceptive agent does not contain estrogen, progesterone, other steroids, or its derivatives.